London Calling 2023: Population-scale nanopore sequencing to further understand the genetics of Alzheimer's disease and related dementias
Previous large-scale genetic sequencing efforts for Alzheimer's disease and related dementias have been performed using short-read sequencing, which is not optimized to identify structural variation or repeat expansions. While long-read sequencing technologies substantially overcome this limitation, they have previously not been considered as a feasible replacement at scale due to being too expensive, not scalable enough, or too error-prone. We developed an efficient and scalable wet lab and computational pipeline for nanopore long-read sequencing. We applied our pipeline to ~300 human brain samples from the North American Brain Expression cohort and demonstrate that this data can be used to phase small and structural variants at megabase scales, better resolve disease-relevant haplotypes, and produce highly accurate haplotype-specific methylation calls. As part of the NIH Center for Alzheimer’s and Related Dementias (CARD) long-read sequencing initiative, we are currently applying this framework to thousands of human brain samples to generate a new long-read resource for the wider research community.